Prognostic performance of IL-6 and IL-10 in febrile pediatric hematology/oncology patients with normal procalcitonin.

INTRODUCTION: It is important to predict adverse outcomes in febrile children with hematology/oncology diseases. Procalcitonin (PCT) is a promising biomarker for the prediction of infection severity, but further studies have revealed its performance in excluding adverse outcomes of infection. IL-6 and IL-10 were reported to have a close association with those infection outcomes. The aim of the study was to investigate the performance of IL-6 and IL-10 in febrile pediatric hematology/oncology patients with normal PCT. METHODS: This was a retrospective study conducted in a tertiary children's hospital in China over the past ten years. Inflammatory biomarkers, including IL-6, IL-10, PCT and C-reactive protein (CRP), were detected at the onset of infection. Separate analyses were conducted in patients with neutropenia and without neutropenia. RESULTS: In total, 5987 febrile cases were enrolled. For patients with neutropenia, IL-6, IL-10 and PCT were significantly increased in patients with bloodstream infection (BSI), gram-negative bacteremia (GNB) and severe sepsis (SS), but only IL-6 and IL-10 were predictive of GNB and SS. For patients without neutropenia, IL-6, IL-10 and PCT were significantly increased in patients with BSI, GNB and SS, but no biomarkers were predictive of adverse outcomes. All biomarkers failed to exclude patients with fever of unknown origin or upper respiratory infection/bronchitis in patients with neutropenia. CONCLUSIONS: IL-6 and IL-10 could be predictors for GNB and SS in febrile patients with neutropenia and had some association with unfavorable outcomes in febrile patients without neutropenia. All biomarkers failed to exclude patients with fever of unknown origin or upper respiratory infection/bronchitis.

The predictive utility of cytokines, procalcitonin and C-reactive protein among febrile pediatric hematology and oncology patients with severe sepsis or septic shock.

Severe sepsis and septic shock are life-threatening for pediatric hematology and oncology patient receiving chemotherapy. Th1/Th2 cytokines, C-reactive protein (CRP), and procalcitonin (PCT) are all thought to be associated with disease severity. The aim of this study was to prospectively verify the utility of Th1/Th2 cytokines and compare them with PCT and CRP in the prediction of adverse outcomes. Data on patients were collected from January 1, 2011, to December 31, 2020. Blood samples were taken for Th1/Th2 cytokine, CRP, and PCT measurements at the initial onset of infection. Severe infection (SI) was defined as severe sepsis or septic shock. Th1/Th2 cytokine levels were determined by using flow cytometric bead array technology. In total, 7,735 febrile episodes were included in this study. For SI prediction, the AUCs of IL-6, IL-10 and TNF-α were 0.814, 0.805 and 0.624, respectively, while IL-6 and IL-10 had high sensitivity and specificity. IL-6 > 220.85 pg/ml and IL-10 > 29.95 pg/ml had high odds ratio (OR) values of approximately 3.5 in the logistic regression. Within the subgroup analysis, for bloodstream infection (BSI) prediction, the AUCs of IL-10 and TNF-α were 0.757 and 0.694, respectively. For multiorgan dysfunction syndrome (MODS) prediction, the AUC of CRP was 0.606. The AUC of PCT for mortality prediction was 0.620. In conclusion, IL-6 and IL-10 provide good predictive value for the diagnosis of SI. For children with SI, IL-10 and TNF-α are associated with BSI, while CRP and PCT are associated with MODS and death, respectively.

Immune microenvironment associated with the severity of Langerhans cell histiocytosis in children.

The aim of this study is to investigate the clinical potential of immune microenvironment in peripheral blood for the severity and therapeutic efficacy of Langerhans cell histiocytosis (LCH). A total of 200 newly diagnosed children with LCH during 10 years was enrolled for analysis in this study. Peripheral blood samples were acquired from patients before treatment in our hospital and immune indicators were detected by a four-color flow cytometer. The levels of CD3 + CD8 + T cell, CD3 + CD4 + HLA-DR + T cell, CD3 + CD8 + HLA-DR + T cell, IL-4, IL-6, IL-10 and IFN-γ in peripheral blood were markedly elevated in LCH patients vs. healthy controls. Patients with multiple system with risk organ involvement (MS-RO + ) exhibited higher levels in IL-6, IL-10 and IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell, compared to those in patients without risk organ involvement (RO-). Patients who responded effectively to initial chemotherapy showed significantly lower levels of IL-4, IL-10, IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell in peripheral blood, compared to those in patients who did not respond to initial chemotherapy. Furthermore, univariate analyses were performed that the higher levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 in peripheral blood were related to non-response in LCH after initial chemotherapy. Immune microenvironment in peripheral blood may be associated with the severity and treatment response of LCH. The levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 may be biomarkers to predict treatment response of LCH patients.

Spectrum and clinical features of gene mutations in Chinese pediatric acute lymphoblastic leukemia.

PURPOSE: The 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85-90%, with a 10-15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL. METHODS: We enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ2-square test or Fisher's exact test for categorical variables. RESULTS: A total of 381 gene mutations were identified in 66 different genes in 152/219 patients. PIK3R1 mutation was more common in infants (P = 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P < 0.001). NRAS, PTPN11, FLT3, and KMT2D mutations were more common in patients who did not carry the fusion genes (all P < 0.050). PTEN mutation was significantly associated with high-risk ALL patients (P = 0.011), while NOTCH1 mutation was common in middle-risk ALL patients (P = 0.039). Patients with ETV6 or PHF6 mutations were less sensitive to steroid treatment (P = 0.033, P = 0.048, respectively). CONCLUSION: This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.

Treatment of Relapsed and Refractory ALK-Positive Anaplastic Large Cell Lymphoma With ALK-Specific Tyrosine Kinase Inhibitor in Children: A Case Series.

Relapsed and refractory ALK-positive anaplastic large cell lymphoma (ALCL) has a poor prognosis. In this report, we present 3 relapsed/refractory pediatric ALCL patients, 1 of these with central nervous system involvement. All 3 patients were treated with ALK inhibitor and achieved complete response. Both crizotinib and alectinib have shown significant activity in pediatric patients with refractory ALK-positive ALCL.

A Novel NUP98/RARG Gene Fusion in Pediatric Acute Myeloid Leukemia Resembling Acute Promyelocytic Leukemia.

Here, we introduced the first case of acute myeloid leukemia (AML) with RARG-NUP98 in a pediatric patient. The young male presented with structural and functional abnormalities similar to hypergranular acute promyelocytic leukemia, but was resistant to all transretinoic acids and arsenic trioxide. Till date, only 12 adult AML cases involving RARG rearrangement have been reported. At present, there is no standardized or optimal treatment option for this AML subtype. Disease management may typically require a joint treatment strategy involving chemotherapy, immunotherapy, and support therapy. In this study, we report the clinical manifestations and experimental results of a 10-year-old male and review other cases of RARG gene rearrangement reported in the literature.

Tuning the ignition of CAR: optimizing the affinity of scFv to improve CAR-T therapy.

How single-chain variable fragments (scFvs) affect the functions of chimeric antigen receptors (CARs) has not been well studied. Here, the components of CAR with an emphasis on scFv were described, and then several methods to measure scFv affinity were discussed. Next, scFv optimization studies for CD19, CD38, HER2, GD2 or EGFR were overviewed, showing that tuning the affinity of scFv could alleviate the on-target/off-tumor toxicity. The affinities of scFvs for different antigens were also summarized to designate a relatively optimal working range for CAR design. Last, a synthetic biology approach utilizing a low-affinity synthetic Notch (synNotch) receptor to achieve ultrasensitivity of antigen-density discrimination and murine models to assay the on-target/off-tumor toxicity of CARs were highlighted. Thus, this review provides preliminary guidelines of choosing the right scFvs for CARs.

Modeling Full-Field Transient Flexural Waves on Damaged Plates with Arbitrary Excitations Using Temporal Vibration Characteristics.

We propose an efficient semi-analytical method capable of modeling the propagation of flexural waves on cracked plate structures with any forms of excitations, based on the same group of vibration characteristics and validated by a non-contact scanning Laser Doppler Vibrometer (LDV) system. The proposed modeling method is based on the superposition of the vibrational normal modes of the detected structure, which can be applied to analyze long-time and full-field transient wave propagations. By connecting the vibration-based transient model to a power flow analysis technique, we further analyze the transient waves on a cracked plate subjected to different excitation sources and show the influence of the damage event on the path of the propagating waves. The experimental results indicate that the proposed semi-analytical method can model the flexural waves, and through that, the crack information can be revealed.

Thyroid Storm Superimposed on Gestational Hypertension: A Case Report and Review of Literature.

A thyroid storm is an extreme manifestation of thyrotoxicosis, and is life threatening without an early diagnosis. Pregnancy or childbirth may worsen maternal hyperthyroidism or induce the development of a thyroid storm. Gestational hypertension, a disorder defined as new-onset hypertension, develops after 20 weeks of gestation and shares symptoms with a thyroid storm. The diagnosis of a thyroid storm may be challenging in patients with gestational hypertension. To highlight the significance of early thyrotoxicosis-related gastrointestinal symptoms, we report a case of a 38-year-old woman with a twin pregnancy, who was diagnosed with gestational hypertension, and then developed a thyroid storm during the peripartum period. She complained of nausea and abdominal pain, followed by tachycardia, hypertension, and a disturbance of consciousness with desaturation. After emergency caesarean section, fever, diarrhea, and high-output heart failure, with pulmonary edema, were noted during the postoperative period in the intensive care unit. The diagnosis of a thyroid storm was confirmed using the Burch-Wartofsky point scale, which was 75 points. In this patient, the uncommon gastrointestinal symptoms, as initial manifestations of thyrotoxicosis, indicated the development of a thyroid storm. The distinguished presentation of thyrotoxicosis-induced cardiomyopathy and peripartum cardiomyopathy also helped in the differential diagnosis between a thyroid storm and gestational hypertension. Aggressive treatment for thyrotoxicosis should not be delayed because of a missed diagnosis.

An Optimized Full-Length FLT3/CD3 Bispecific Antibody Demonstrates Potent Anti-leukemia Activity and Reversible Hematological Toxicity.

FLT3 (FMS-like tyrosine kinase 3), expressed on the surface of acute myeloid leukemia (AML) blasts, is a promising AML target, given its role in the development and progression of leukemia, and its limited expression in tissues outside the hematopoietic system. Small molecule FLT3 kinase inhibitors have been developed, but despite having clinical efficacy, they are effective only on a subset of patients and associated with high risk of relapse. A durable therapy that can target a wider population of AML patients is needed. Here, we developed an anti-FLT3-CD3 immunoglobulin G (IgG)-based bispecific antibody (7370) with a high affinity for FLT3 and a long half-life, to target FLT3-expressing AML blasts, irrespective of FLT3 mutational status. We demonstrated that 7370 has picomolar potency against AML cell lines in vitro and in vivo. 7370 was also capable of activating T cells from AML patients, redirecting their cytotoxic activity against autologous blasts at low effector-to-target (E:T) ratio. Additionally, under our dosing regimen, 7370 was well tolerated and exhibited potent efficacy in cynomolgus monkeys by inducing complete but reversible depletion of peripheral FLT3+ dendritic cells (DCs) and bone marrow FLT3+ stem cells and progenitors. Overall, our results support further clinical development of 7370 to broadly target AML patients.

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children.

CD19 chimeric antigen receptor T (CD19CAR-T) cell therapy has shown striking response in treating relapsed and refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, side-effects including cytokine release syndrome (CRS) and neurotoxicity can be fatal to patients. In this report, five patients with r/r B-ALL were treated with CD19CAR-T cells. Cytokine release syndrome experienced by four patients who achieved complete remission (CR) with minimal residual disease (MRD) negative. One patient who did not response to the treatment had no CRS. Acute toxicities including fever, hypotension and other neurological toxicities occurred in responding patients within 2 weeks post infusion and managed properly with tocilizumab and/or steroids according to the "real-time" monitoring of a simple 6 Th1/Th2 cytokine pattern. In conclusion, our study demonstrates that CD19CAR-T cell therapy can be safely administered for patients with relapsed and refractory leukemia under the "real-time" monitoring of a simple 6-cytokine pattern.

Minimal Residual Disease-guided Risk Restratification and Therapy Improves the Survival of Childhood Acute Lymphoblastic Leukemia: Experience From a Tertiary Children's Hospital in China.

The minimal residual disease (MRD) has been shown to be very important to evaluate the prognostic significance in childhood acute lymphoblastic leukemia (ALL), but the impact under the current treatment protocol in China has not been fully elucidated. The aim of this study was to investigate the efficacy of MRD-guided risk restratification of ALL. A total of 676 children with ALL were enrolled. In the predictive study group, 476 patients were enrolled with 5-year cumulative incidence of relapse rates of the low-risk (LR), intermediate-risk (IR), and high-risk groups being 11.0%±2.3%, 12.6%±3.3%, and 32.7%±4.9%, respectively. In the intervention study group, 19/200 patients enrolled were reclassified into risk groups according to the MRD levels. The 3-year event-free survival and overall survival were 85.2%±2.9% and 90.6%±2.1%, respectively, which were higher than those of the predictive study group (79.1%±1.9% and 84.7%±1.7%, respectively; P<0.05). The 3-year cumulative incidence of relapse in the LR and IR groups of the intervention study group were 4.2%±3.1% and 6.4%±3.1%, respectively, which were significantly lower than those in the predictive study group (7.2%±1.8% and 11.8%±3.2%, respectively; P<0.05). We conclude that the risk of relapse in the LR and IR groups can be significantly reduced after MRD-guided risk restratification.

Antibody-Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrate Improved Homogeneity and Other Pharmacological Properties over Conventional Heterogeneous ADCs.

Conventional antibody-drug conjugates (ADCs) are heterogeneous mixtures of chemically distinct molecules that vary in both drugs/antibody (DAR) and conjugation sites. Suboptimal properties of heterogeneous ADCs have led to new site-specific conjugation methods for improving ADC homogeneity. Most site-specific methods require extensive antibody engineering to identify optimal conjugation sites and introduce unique functional groups for conjugation with appropriately modified linkers. Alternative nonrecombinant methods have emerged in which bifunctional linkers are utilized to cross-link antibody interchain cysteines and afford ADCs containing four drugs/antibody. Although these methods have been shown to improve ADC homogeneity and stability in vitro, their effect on the pharmacological properties of ADCs in vivo is unknown. In order to determine the relative impact of interchain cysteine cross-linking on the therapeutic window and other properties of ADCs in vivo, we synthesized a derivative of the known ADC payload, MC-MMAF, that contains a bifunctional dibromomaleimide (DBM) linker instead of a conventional maleimide (MC) linker. The DBM-MMAF derivative was conjugated to trastuzumab and a novel anti-CD98 antibody to afford ADCs containing predominantly four drugs/antibody. The pharmacological properties of the resulting cross-linked ADCs were compared with analogous heterogeneous ADCs derived from conventional linkers. The results demonstrate that DBM linkers can be applied directly to native antibodies, without antibody engineering, to yield highly homogeneous ADCs via cysteine cross-linking. The resulting ADCs demonstrate improved pharmacokinetics, superior efficacy, and reduced toxicity in vivo compared to analogous conventional heterogeneous ADCs.

The effect of the plasma methotrexate concentration during high-dose methotrexate therapy in childhood acute lymphoblastic leukemia.

Two hundred and thirty-one acute lymphoblastic leukemia (ALL) children with 1376 high-dose methotrexate (HD-MTX) courses (3-5 g/m2) were enrolled to analyze the influence of the plasma MTX concentration (CMTX) in ALL. The 24-h target peak CMTX (C24h) was set at 33 µmol/l for low-risk (LR) and 65 µmol/l for intermediate/high-risk (IR/HR) groups. The median C24h was 42.0 µmol/l and 69.7 µmol/l for LR and IR/HR groups, respectively. MTX excretion delay was observed in 14.6% of courses, which was more frequent in IR/HR groups (56.9% vs. LR group 40.2%, p = .014) and T-ALL patients (82.6% vs. B-ALL 47.1%, p = .001). MTX-related toxicities were more common in courses with MTX excretion delay. However, survival between the patients who failed to reach the target C24h or not, with or without MTX excretion delay, was comparable. These findings suggest that, owing to the effectiveness of risk stratification chemotherapy, CMTX does not exert an independent influence on the prognosis of childhood ALL.

IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rßγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.

A multiplex cytokine score for the prediction of disease severity in pediatric hematology/oncology patients with septic shock.

Although many inflammatory cytokines are prognostic in sepsis, the utility of cytokines in evaluating disease severity in pediatric hematology/oncology patients with septic shock was rarely studied. On the other hand, a single particular cytokine is far from ideal in guiding therapeutic intervention, but combination of multiple biomarkers improves the accuracy. In this prospective observational study, 111 episodes of septic shock in pediatric hematology/oncology patients were enrolled from 2006 through 2012. Blood samples were taken for inflammatory cytokine measurement by cytometric bead array (CBA) technology at the initial onset of septic shock. Interleukin (IL)-6 and IL-10 were significantly elevated in majority of patients, while tumor necrosis factor (TNF)-α and interferon (IFN)-γ were markedly increased in patients with high pediatric index of mortality 2 (PIM2) score and non-survivors. All the four cytokines paralleled the PIM2 score and differentially correlated with hemodynamic disorder and fatal outcomes. The pediatric multiplex cytokine score (PMCS), which integrated the four cytokines into one score system, was related to hemodynamic disorder and mortality as well, but showed more powerful prediction ability than each of the four cytokines. PMCS was an independent predictive factor for fatal outcome, presenting similar discriminative power with PIM2, with accuracy of 0.83 (95% CI, 0.71-0.94). In conclusion, this study develops a cytokine scoring system based on CBA technique, which performs well in disease severity and fatality prediction in pediatric hematology/oncology patients with septic shock.

Inserting EF1α-driven CD7-specific CAR at CD7 locus reduces fratricide and enhances tumor rejection.

CAR-T therapies to treat T-cell malignancies face unique hurdles. Normal and malignant T cells usually express the same target for CAR, leading to fratricide. CAR-T cells targeting CD7, which is expressed in various malignant T cells, have limited expansion due to fratricide. Using CRISPR/Cas9 to knockout CD7 can reduce the fratricide. Here we developed a 2-in-1 strategy to insert EF1α-driven CD7-specific CAR at the disrupted CD7 locus and compared it to two other known strategies: one was random integration of CAR by a retrovirus and the other was site-specific integration at T-cell receptor alpha constant (TRAC) locus, both in the context of CD7 disruption. All three types of CD7 CAR-T cells with reduced fratricide could expand well and displayed potent cytotoxicity to both CD7+ tumor cell lines and patient-derived primary tumors. Moreover, EF1α-driven CAR expressed at the CD7 locus enhances tumor rejection in a mouse xenograft model of T-cell acute lymphoblastic leukemia (T-ALL), suggesting great clinical application potential. Additionally, this 2-in-1 strategy was adopted to generate CD7-specific CAR-NK cells as NK also expresses CD7, which would prevent contamination from malignant cells. Thus, our synchronized antigen-knockout CAR-knockin strategy could reduce the fratricide and enhance anti-tumor activity, advancing clinical CAR-T treatment of T-cell malignancies.

Minimal residual disease detection by next-generation sequencing of different immunoglobulin gene rearrangements in pediatric B-ALL.

While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL) has been reported, the contribution of light chain loci (IGK/IGL) remains elusive. This study is to evaluate the prognosis of IGH and IGK/IGL rearrangement-based MRD detected by next-generation sequencing in B-ALL at the end of induction (EOI) and end of consolidation (EOC). IGK/IGL rearrangements identify 5.5% of patients without trackable IGH clones. Concordance rates for IGH and IGK/IGL are 79.9% (cutoff 0.01%) at EOI and 81.0% (cutoff 0.0001%) at EOC, respectively. Patients with NGS-MRD < 0.01% at EOI or <0.0001% at EOC present excellent outcome, with 3-year event-free survival rates higher than 95%. IGH-MRD is prognostic at EOI/EOC, while IGK-MRD at EOI/EOC and IGL-MRD at EOI are not. At EOI, NGS identifies 26.2% of higher risk patients whose MRD < 0.01% by flow cytometry. However, analyzing IGK/IGL along with IGH fails to identify additional higher risk patients both at EOI and at EOC. In conclusion, IGH is crucial for MRD monitoring while IGK and IGL have relatively limited value.

CD38-Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells.

The robust and stable expression of CD38 in T-cell acute lymphoblastic leukemia (T-ALL) blasts makes CD38 chimeric antigen receptor (CAR)-T/natural killer (NK) a potential therapy for T-ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR-T/NK cells. Here a "2-in-1" gene editing strategy is developed to generate fratricide-resistant locus-specific CAR-T/NK cells. CD38-specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI ) or exogenous EF1α promoter (CD38KO/KI EF1α). CD38 knockout reduces fratricide and allows the expansion of CAR-T cells. Meanwhile, CD38KO/KI EF1α results in higher CAR expression than CD38KO/KI in both CAR-T and CAR-NK cells. In a mouse T-ALL model, CD38KO/KI EF1α CAR-T cells eradicate tumors better than CD38KO/KI CAR-T cells. Surprisingly, CD38KO/KI CAR-NK cells show superior tumor control than CD38KO/KI EF1α CAR-NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR-T and CAR-NK cells differently. Therefore, these results support the efficacy of CD38 CAR-T/NK against T-ALL and demonstrate that the "2-in-1" strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation.

Th1/Th2 cytokine profiles in G+/G- bacteremia in pediatric hematology/oncology patients.

BACKGROUND: Early diagnosis of infection and appropriate choice of antibiotics are essential not only to improve the prognosis of the patients but also to prevent from the abuse of the antibiotics in hematology/oncology children at the time of neutropenia after intensive chemotherapy. PROCEDURE: We evaluated the quantification of Th1/Th2 cytokines with flow cytometry bead assay (CBA) in 145 hospitalized febrile hematology/oncology children with positive blood culture to seek for a rapid diagnostic method to determine the type of infection. RESULTS: IL-4, IL-6, IL-10, TNF-α, and IFN-γ levels from both G- and G+ bacteremia groups were significantly higher than those of controls (P < 0.001). The median levels of IL-6, IL-10, TNF-α of Group G- were 525.4, 96.0, and 6.9 pg/ml, respectively, significantly higher than those of Group G+ (150.0, 22.6, and 4.5 pg/ml, respectively, P < 0.001). According to the different degrees of increased IL-6 and IL-10 levels, we named the G- bacterial infection related cytokine profile G- BIRCP and the G+ BIRCP. The specificity and sensitivity of BIRCP prediction for G- and G+ bacteria cultures were 60.2% and 75.4%, 66.8% and 70.1%, respectively. Similar therapeutic efficacy was achieved between BIRCP-based and broad-spectrum antibiotics groups (86.1% vs. 89.3%, P > 0.05), which was significantly increased as compared with that (65.5%, P < 0.05) of empirical group. CONCLUSIONS: These results showed the promising use of the IL-6/IL-10/TNF-α determination with CBA technology for the early and rapid diagnosis, evaluation of G+/G- bacteremia in pediatric hematology/oncology patients.